In his major league debut, he pitched one scoreless inning, only giving up a leadoff single to Kenny Lofton.

[8] Blackburn pitched 16 innings in spring training for the Twins, posting a 2.25 ERA, earning him a starting spot on the 2008 rotation.

[9] He picked up his first major league win on April 19, 2008, against the Cleveland Indians, pitching 7.2 innings of shutout baseball.

[10] On May 1, 2008, Blackburn was hit in the face by a line drive off the bat of New York Yankees outfielder Bobby Abreu;[11] Though he did not miss any time, he said in early 2009 that the incident affected him mentally on the mound for the rest of the season.

[14] After the Twins and the Chicago White Sox ended the season with 88–74 records to top the AL Central, Blackburn started the one-game tiebreaker to determine the division winner.

[14] On March 7, 2010, Blackburn signed a four-year, $14 million contract extension with the Twins that included a club option for 2014.

[17] However, he struggled after that, going 1–6 with a 9.88 ERA over his next nine starts, and on July 21, 2010, Blackburn was demoted to the bullpen and replaced in the rotation by Brian Duensing.

[17] On July 29, the Twins optioned Blackburn to Triple-A Rochester to make room on the active roster for newly acquired closer Matt Capps.

After walking Chone Figgins in the bottom of the ninth, he was relieved and Brian Fuentes struck out Russell Branyan.

[14] On October 25, 2012, Blackburn had successful surgery to remove a bone chip in his throwing elbow, and was on track to return for spring training.

[4] After being released by the Twins in late 2013, Blackburn encountered problems with his surgically repaired knee which he had surgery on in August.